Interstitial cystitis (IC) is a chronic bladder disease characterized by urinary frequency/urgency and suprapubic pain. There are currently no consistently effective treatments for IC available. The long-range objective of this research is to develop a better understanding of the pathophysiological mechanisms of the pain aspects of IC, in order to develop improved treatment strategies. Clinical, immunologic and neurobiologic characteristics all support the hypothesis that IC is a heterogeneous syndrome. The proposed studies are based on two clinical observations: First, IC shares many characteristics with other chronic visceral pain syndromes. In addition, many patients with IC report extra-bladder pain symptoms, such as gastrointestinal, pelvic and chronic somatic pain. This clinical impression has been confirmed by a series of epidemiological studies. These observations suggest that there might be generalized alterations in pain modulatory mechanisms in IC. Second, IC affects predominantly women in their reproductive ages. This observation suggests that the proposed alterations in nociceptive processing in IC might be further modulated by the gonadal hormonal milieu. The working hypotheses for this proposal are that (1) a spectrum of different insults can lead to chronic pain in patients suffering from IC, (2) different underlying pathogenic pain mechanisms may require different treatment strategies for patients diagnosed with IC, (3) multiple different pathogenic pain mechanisms may coexist in the same patient. The following aims address these hypotheses: Aim 1: We propose to characterize patients with IC in detail using neurophysiological (measures of nociceptive function), autonomic and psychological parameters, urine markers of bladder epithelial function and cytokine profiles (urine, blood). Aim 2: We will determine the influence of the gonadal hormonal milieu on symptoms of the disease in women with IC. We expect that patients with IC can be differentiated into distinct sub-groups, based on the parameters tested. The results of these studies should have rapid clinical implications: if subsets of patients with different IC etiologies can be identified, then they can be targeted for focused research and specific treatments.